Suppression of azoxymethane-induced colon cancer development in rats by a prostaglandin E receptor EP1-selective antagonist

Prostaglandin E-2 is involved in colon carcinogenesis through its binding to the PGE(2) receptor subtypes EP1, EP2, EP3 and EP4. We have demonstrated that administration of ONO-8711, an EP1-selective antagonist, suppresses development of AOM-induced ACF in C57BL/ 6 mice and F344 rats. ONO-8711 also reduced the numbers of intestinal polyps in Min mice. In the present study, we investigated the long-term effects of ONO-8711 on colon cancer development in rats treated with AOM. Male F344 rats were injected subcutaneously with AOM (115 mg/kg body weight) once a week for the first 2 weeks to develop colon cancer. Administration of 400 or 800 p.p.m.. ONO-8711 in their diets for 32 weeks reduced the incidence, multiplicity and volume of colon carcinomas. The incidence of colon adenocarcinomas in AOM-treated rats was 97, 83 and 76% (P < 0.05) in the 0, 400 and 800 p.p.m. of ONO-8711 groups, respectively. The multiplicity of adenocarcinomas was also decreased significantly, being 3.31 +/- 0.33, 2.34 +/- 0.27 (P < 0.05) and 2.06 +/- 0.34 (P < 0.01) with 0, 400 and 800 p.p.m. of ONO-8711, respectively. Moreover, treatment with 800 p.p.m. ONO-8711 reduced the mean volume of adenocarcinomas to 49% (P < 0.05) of the value for the AOM treatment alone. Furthermore, the BrdU labeling index was decreased significantly in colon cancer cells by 800 p.p.m. ONO-8711. These results confirm that EP1 is involved in colon carcinogenesis and that EP1-selective antagonists might be promising candidates for colon cancer chemopreventive agents.